This is an application for a KO5 Senior Scientist Award to support Dr. Patricia H. Reggio and her longstanding program in research, education and academic development devoted to understanding the determinants for the action of the cannabinoids at a molecular level. Dr. Reggie's laboratory is currently funded through March 2008 (RO1 DA03934) for a multidisciplinary project entitled, "Molecular Determinants of Cannabinoid Activity," This project is in its twentieth year of NIDA support. Dr. Reggio currently has a KO2 award from NIDA (KO2 DA000489) which ends in August 2006. This award has permitted the reduction of significant teaching and service responsibilities such that she could devote 75% of her time to research over the KO2 project period. The KO2 award has also facilitated the acquisition of significant new methodology, including lipid bilayer simulation and dimer interface prediction methodology, that has greatly expanded the breadth of research in Dr. Reggie's lab. Under the plan detailed in this KO5 application, Dr. Reggio will be able to continue to focus 75% of her time on research, while maintaining her mentorship and leadership activities, as well as her career development. The Research Plan outlines a collaborative, multidisciplinary project that involves the application of state-of the- art methods for molecular simulation and structure-function analysis, as well as, the implementation of new tools in bioinformatics. This plan includes two emphases: Ligand-Receptor Recognition and Ligand- Induced Receptor Activation/lnactivation and will focus not only on the CB1 and CB2 receptors, but also on a new putative cannabinoid receptor, GPR55. At each step, the computational aspects of this project will be aided and supplemented by collaboration with experimental medicinal chemists, pharmacologists and molecular biologists. Hypotheses generated via molecular simulation will be tested by compound synthesis and pharmacological evaluation. Key receptor residues and interactions identified through receptor modeling studies will be tested via mutation and functional studies. Experimental information will be used to refine receptor models such that at any given time, these models reflect the current state of knowledge in the cannabinoid field. Information about cannabinoid receptor structure and binding modes of ligands will aid in fundamental structure-function studies of this important class of receptors and will also aid in the design of improved therapeutic agents based on the cannabinoids.